8wy3

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 21Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 21

Structural highlights 8wy3 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.78Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein. Function BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMed Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan-BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC(50) = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC(50) = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (23: 2583-fold; 10: 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis in vitro. Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC(50) > 30 muM) mitigated the inhibition of the human ether-a-go-go-related gene (hERG) ion channel compared with 10 (hERG IC(50) = 2.8 muM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents. Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.,Jiang W, Hou Q, Xu H, Yang K, Wang X, Zhang K, Zeng Y, Li W, Wang B, Luo G, Zhao X, Shen H, Xu Y, Wu X J Med Chem. 2024 Jan 4. doi: 10.1021/acs.jmedchem.3c02104. PMID:38175809 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 8wy3, resolution 2.78Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image